The development of autoimmune disease in man and animals has clearly been shown to be under genetic control. The spontaneous animal models, NZB and MRL provide one of the most suitable systems to further analyze the genetic basis of the various immunological abnormalities in these mice. It is now apparent that marked cellular defects in specific subpopulations of lymphoid cells are involved in the pathogenesis of disease in these mice. This proposal involves a detailed genetic analysis of the various defects, both in terms of number, linkage and cellular expression for each specific defect but also a detailed analysis of the possible genetic association between the various abnormalities. Emphasis will be placed on quantitative analysis of the various lymphoid subpopulations in these animals using flow micro-fluorometry, and the sorting of defined populations to assess their functional activities.